Gemfibrozil (GEM), a lipid regulator, is a fibric acid derivative widely used in the treatment of hyperlipidemia. It has been reported that GEM can induce acute liver injury in the course of therapy in clinical practice, so it is necessary to elucidate the mechanisms of toxic action. The present study focused on metabolic activation of GEM, possibly participating in GEM-mediated liver injury. A benzylic alcohol metabolite (M1), along with a phenol metabolite (M2), was detected in microsomal incubations, rat primary hepatocyte culturing, and rats given GEM. A GSH conjugate (M3) was detected in cultured rat hepatocytes after exposure to GEM. Formation of M1 was found to be NADPH dependent, and generation of M3 required M1 and 3′-phosphoadenosine-5′phosphosulfate. It is most likely that GEM was biotransformed to M1, which was further metabolized to a sulfate. The resulting sulfate was reactive to bio-thiols. Cytochrome P450 and sulfotransferases participated in the phase I and phase II reactions, respectively. M1 and M3 were chemically synthesized, and their structures were characterized by mass spectrometry and NMR. The present study has particular value for elucidating the mechanism of liver injury caused by GEM.
Carbendazim
(CBZ) is a broad-spectrum fungicide widely used in
many nations for foliar spray as well as seed and soil treatment.
The resulting contamination and environmental pollution have been
drawing public attention. In particular, CBZ was reported to cause
liver damage in rats and zebrafish, and the mechanisms of its toxicity
have not been clarified. The purposes of this study were to investigate
the metabolic activation of CBZ and to determine a possible role of
the reactive metabolites in CBZ-induced liver injury reported. One
oxidative metabolite (M1), one glutathione conjugate (M2), and one N-acetyl cysteine conjugate (M3) were detected in human
and rat liver microsomal incubations fortified with glutathione or N-acetyl cysteine after exposure to CBZ. CYP1A2 was the
major enzyme responsible for the metabolic activation of CBZ. Biliary
M2 and urinary M3 were detected in rats treated with CBZ. CBZ-derived
protein adduction was found in cultured rat primary hepatocytes treated
with CBZ. The increase of administration concentration intensified
not only the cytotoxicity but also protein adduction induced by CBZ,
suggesting a correlation of the cytotoxicity with the observed protein
modification. The findings facilitate the understanding of the mechanisms
of toxic action of CBZ.
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